This invention relates to a process for preparing .beta.-hydroxy-.alpha.-amino acids. In particular it relates to an enzymatic process for preparing .beta.-hydroxy-.alpha.-amino acids substantially in the L-erythro-form.
The .beta.-hydroxy-.alpha.-amino acids have many uses including use as intermediates in the preparation of .beta.-lactam antibiotics. See, for example, Mattingly, P. G.; Miller, M. J., J. Org. Chem. 1981, 46, 1557 and Miller, M. J., et al. J. Am. Chem. Soc. 1980, 102, 7026. A number of chemical methods for the preparation of .beta.-hydroxy-.alpha.-amino acids are known, however, most have one or more disadvantages. These include a lack of generality, poor stereochemical control, requirement of chiral auxiliaries, or production of primarily the threo (or syn) isomers.
Enzymatic processes have some distinct advantages over chemical processes. For example, they are carried out in aqueous systems under mild conditions and, frequently are stereoselective. The enzyme employed in the process of the invention is known generally as an aldolase. One such aldolase is serine hydroxymethyltransferase (SHMT), Schirch, L. Adv. Enzymol. Relat. Areas Mol. Biol. 1982, 53, 83 and Schirch, L.; Gross, T. J. Biol. Chem. 1968, 243, 5651. The natural biological roles of the aldolases involve the transfer of one-carbon units to or from serine and the retroaldol cleavage of .beta.-hydroxy-.alpha.-amino acids such as threonine and allo-threonine to generate an aldehyde and glycine.
The aldolases are ubiquitous in plants, bacteria and animals, for example, corn seedlings, mung bean seedlings, and rabbit liver. The process of this invention comprises the use of SHMT to elaborate, under mild conditions, .beta.-hydroxy-.alpha.-amino acid precursors to .beta.-lactam antibiotics. The process provides in numerous instances the .beta.-hydroxy amino acid in the L-erythro isomeric form which is the desired from of the precursor providing the correct diastereomeric form of the .beta.-lactam antibiotic.